Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior.

Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglial Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglial BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administering doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological function in the mPFC, whereas normalizing BDNF from later ages (p45-p50) did not normalize electrophysiological abnormalities in the mPFC, despite the improved sociability. To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible proxy for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. In summary, our study demonstrated the influence of microglial BDNF on the development of experience-dependent social behaviors in mice, emphasizing its specific impact on the maturation of mPFC function, particularly during the juvenile period. Furthermore, our results propose a translational implication by suggesting a potential link between BDNF secretion from macrophages and childhood experiences in humans.

Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior.

Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglia Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglia BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administration of doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological functions; this was not observed when BDNF was normalized from a later age (p45-p50). To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible substitute for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. Thus, microglia BDNF might regulate sociability and mPFC maturation in mice during the juvenile period. Furthermore, childhood experiences in humans may be related to BDNF secretion from macrophages.

Exploration of electroencephalogram response to MPH treatment in ADHD patients.

Attention-deficit/hyperactivity disorder (ADHD) is known to be associated with several diagnostic resting-state electroencephalography (EEG) patterns, including the theta/beta ratio, but no objective predictive markers for each medication. In this study, we explored EEG markers with which the therapeutic efficacy of medications could be estimated at the 1st clinical visit. Thirty-two ADHD patients and thirty-one healthy subjects participated in this study. EEG was recorded during eyes-closed resting conditions, and ADHD symptoms were scored before and after the therapeutic intervention (8 ± 2 weeks). Although comparing EEG patterns between ADHD patients and healthy subjects showed significant differences, EEG dynamics, e.g., theta/beta ratio, in ADHD patients before and after MPH treatment were not significantly different despite improvements in ADHD symptoms. We demonstrated that MPH good responders and poor responders, defined by the efficacy of MPH, had significantly different theta band power in right temporal areas, alpha in left occipital and frontal areas, and beta in left frontal areas. Moreover, we showed that MPH good responders had significant improvements toward normalization in several coherence measures after MPH treatment. Our study implies the possibility of these EEG indices as predictive markers for ADHD therapeutic efficacy.

Association of adverse childhood experience-related increase in neurite density with sensory over-responsivity in autism spectrum disorder: A neurite orientation dispersion and density imaging study.

Sensory over-responsivity (SOR) causes social and daily distress in individuals with autism spectrum disorder (ASD). Compared to typically developed (TD) individuals, ASD individuals are at higher risk of adverse childhood experiences (ACEs), which induce abnormal neuronal development. However, whether or how ACEs are associated with abnormal neural development and SOR in ASD remains to be determined. Forty-five individuals with ASD and 43 TD individuals underwent T1-weighted and neurite orientation dispersion and density imaging; the axonal and dendritic densities were defined as the neurite density index (NDI). Voxel-based analyses were performed to explore the brain regions associated with SOR. The relationships between severity of ACEs and SOR, and NDI in the brain regions were examined. ASD individuals showed a significantly positive association between SOR severity and NDI in the right superior temporal gyrus (STG), which was not found in TD individuals. Severity of ACEs correlated significantly with that of SOR and NDI in the right STG in ASD; ASD individuals having severe SOR showed significantly higher NDI in the right STG than those with mild SOR and TD individuals. In individuals with ASD, NDI in the right STG, but not ACEs, could predict the severity of SOR, which was not shown in TD subjects. Our findings suggest that severe ACEs are involved in excessive neurite density in the right STG in ASD. ACE-associated excessive neurite density in the right STG is critical for SOR in ASD, which may be a therapeutic target in the future.

Juvenile social isolation immediately affects the synaptic activity and firing property of fast-spiking parvalbumin-expressing interneuron subtype in mouse medial prefrontal cortex.

A lack of juvenile social experience causes various behavioral impairments and brain dysfunction, especially in the medial prefrontal cortex (mPFC). Our previous studies revealed that juvenile social isolation for 2 weeks immediately after weaning affects the synaptic inputs and intrinsic excitability of fast-spiking parvalbumin-expressing (FSPV) interneurons as well as a specific type of layer 5 (L5) pyramidal cells, which we termed prominent h-current (PH) cells, in the mPFC. However, since these changes were observed at the adult age of postnatal day 65 (P65), the primary cause of these changes to neurons immediately after juvenile social isolation (postnatal day 35) remains unknown. Here, we investigated the immediate effects of juvenile social isolation on the excitability and synaptic inputs of PH pyramidal cells and FSPV interneurons at P35 using whole-cell patch-clamp recording. We observed that excitatory inputs to FSPV interneurons increased immediately after juvenile social isolation. We also found that juvenile social isolation increases the firing reactivity of a subtype of FSPV interneurons, whereas only a fractional effect was detected in PH pyramidal cells. These findings suggest that juvenile social isolation primarily disturbs the developmental rebuilding of circuits involving FSPV interneurons and eventually affects the circuits involving PH pyramidal cells in adulthood.

Transdiagnostic comparisons of intellectual abilities and work outcome in patients with mental disorders: multicentre study.

BACKGROUND: Cognitive impairment is common in people with mental disorders, leading to transdiagnostic classification based on cognitive characteristics. However, few studies have used this approach for intellectual abilities and functional outcomes. AIMS: The present study aimed to classify people with mental disorders based on intellectual abilities and functional outcomes in a data-driven manner. METHOD: Seven hundred and forty-nine patients diagnosed with schizophrenia, bipolar disorder, major depression disorder or autism spectrum disorder and 1030 healthy control subjects were recruited from facilities in various regions of Japan. Two independent k-means cluster analyses were performed. First, intelligence variables (current estimated IQ, premorbid IQ, and IQ discrepancy) were included. Second, number of work hours per week was included instead of premorbid IQ. RESULTS: Four clusters were identified in the two analyses. These clusters were specifically characterised in terms of IQ discrepancy in the first cluster analysis, whereas the work variable was the most salient feature in the second cluster analysis. Distributions of clinical diagnoses in the two cluster analyses showed that all diagnoses were unevenly represented across the clusters. CONCLUSIONS: Intellectual abilities and work outcomes are effective classifiers in transdiagnostic approaches. The results of our study also suggest the importance of diagnosis-specific strategies to support functional recovery in people with mental disorders.

Expression of actin- and oxidative phosphorylation-related transcripts across the cortical visuospatial working memory network in unaffected comparison and schizophrenia subjects.

Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by a distributed cortical network. In one node of this network, the dorsolateral prefrontal cortex (DLPFC), altered expression of transcripts for actin assembly and mitochondrial oxidative phosphorylation (OXPHOS) have been reported in SZ. To understand the relationship between these processes, and the extent to which similar alterations are present in other regions of vsWM network in SZ, a subset of actin- (CDC42, BAIAP2, ARPC3, and ARPC4) and OXPHOS-related (ATP5H, COX4I1, COX7B, and NDUFB3) transcripts were quantified in DLPFC by RNA sequencing in 139 SZ and unaffected comparison (UC) subjects, and in DLPFC and three other regions of the cortical vsWM network by qPCR in 20 pairs of SZ and UC subjects. By RNA sequencing, levels of actin- and OXPHOS-related transcripts were significantly altered in SZ, and robustly correlated in both UC and SZ subject groups. By qPCR, cross-regional expression patterns of these transcripts in UC subjects were consistent with greater actin assembly in DLPFC and higher OXPHOS activity in primary visual cortex (V1). In SZ, CDC42 and ARPC4 levels were lower in all regions, BAIAP2 levels higher only in V1, and ARPC3 levels unaltered across regions. All OXPHOS-related transcript levels were lower in SZ, with the disease effect decreasing from posterior to anterior regions. The differential alterations in markers of actin assembly and energy production across regions of the cortical vsWM network in SZ suggest that each region may make specific contributions to vsWM impairments in the illness.

Discontinuation and remission rates and social functioning in patients with schizophrenia receiving second-generation antipsychotics: 52-week evaluation of JUMPs, a randomized, open-label study.

AIM: Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety. RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin. CONCLUSION: All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan.

Developmental dysregulation of excitatory-to-inhibitory GABA-polarity switch may underlie schizophrenia pathology: A monozygotic-twin discordant case analysis in human iPS cell-derived neurons.

Schizophrenia is a major psychiatric disorder, but the molecular mechanisms leading to its initiation or progression remain unclear. To elucidate the pathophysiology of schizophrenia, we used an in vitro neuronal cell culture model involving human induced pluripotent stem cells (hiPSCs) derived from a monozygotic-twin discordant schizophrenia pair. The cultured neurons differentiated from hiPSCs were composed of a mixture of glutamatergic excitatory neurons and gamma aminobutyric acid (GABA)ergic inhibitory neurons. In the electrophysiological analysis, a different pattern of spontaneous neuronal activity was observed under the condition without any stimulants. The frequency of spontaneous excitatory post-synaptic currents (sEPSCs) was significantly higher in the hiPSC-derived neurons of the patient with schizophrenia than in the control sibling at day-in-vitro 30. However, the synaptic formation was not different between the patient with schizophrenia and the control sibling during the same culture period. To explain underlying mechanisms of higher excitability of presynaptic cells, we focused on the potassium-chloride co-transporter KCC2, which contributes to excitatory-to-inhibitory GABA polarity switch in developing neurons. We also revealed the altered expression pattern of KCC2 in hiPSC-derived neurons from the patient with schizophrenia, which could contribute to understanding the pathology of schizophrenia in the developing nervous system.

Tumor necrosis factor-α expression aberration of M1/M2 macrophages in adult high-functioning autism spectrum disorder.

The etiology of autism spectrum disorder (ASD) is complex, and its pathobiology is characterized by enhanced inflammatory activities; however, the precise pathobiology and underlying causes of ASD remain unclear. This study was performed to identify inflammatory indicators useful for diagnosing ASD. The mRNA expression of cytokines, including tumor necrosis factor-α (TNF-α), was measured in cultured M1 and M2 macrophages from patients with ASD (n = 29) and typically developed (TD) individuals (n = 30). Additionally, TNF-α expression in the monocytes of patients with ASD (n = 7), showing aberrations in TNF-α expression in M1/M2 macrophages and TD individuals (n = 6), was measured. TNF-α expression in M1 macrophages and the TNF-α expression ratio in M1/M2 macrophages were markedly higher in patients with ASD than in TD individuals; however, this increase was not observed in M2 macrophages (M1: sensitivity = 34.5%, specificity = 96.7%, area under the curve = 0.74, positive likelihood ratio = 10.34; ratio of M1/M2: sensitivity = 55.2%, specificity = 96.7%, area under the curve = 0.79, positive likelihood ratio = 16.55). Additionally, TNF-α expression in monocytes did not significantly differ between patients with ASD and TD individuals. In conclusion, further studies on TNF-α expression in cultured macrophages may improve the understanding of ASD pathobiology. LAY SUMMARY: TNF-α expression in differentiated M1 macrophages and TNF-α expression ratio in differentiated M1/M2 macrophages were markedly higher in patients with ASD than in TD individuals, while no difference in TNF-α expression was found in pre-differentiation cells such as monocytes. These measurements allow elucidation of the novel pathobiology of ASD and can contribute to biomarker implementation for the diagnosis of adult high-functioning ASD.

Effects of an attachment-based parent intervention on mothers of children with autism spectrum disorder: preliminary findings from a non-randomized controlled trial.

BACKGROUND: Caregivers of children with autism spectrum disorders (ASD) often experience difficulties in responding appropriately to the needs of those children, who typically express attachment in distinct and nonconventional ways. This highlights the need for an attachment-based approach targeted at caregivers of children with ASD. Circle of Security Parenting (COSP), an attachment-based parenting program, is designed to increase caregivers' sensitivity to children's attachment needs. The aim of this study was to provide verification of the effectiveness of COSP in mothers of children with ASD. METHODS: This study was a non-randomized controlled trial. Sixty mothers of children with ASD aged 4-12 were recruited. Twenty mothers received the COSP intervention, while 40 did not. The characteristics of children in the control group were matched with those of the intervention group. To evaluate the outcomes of the intervention, changes in parental self-efficacy and mental health were assessed using the Tool to Measure Parenting Self-Efficacy (TOPSE) and the General Health Questionnaire-30 (GHQ-30). The children's improvement in emotional and behavioral problems was assessed from the mothers' perspective using the Child Behavior Checklist (CBCL). Both groups completed the assessments in parallel. Evaluations were compared between baseline (T1) and 6-month follow-up (T2). RESULTS: Scores for self-efficacy and mental health of mothers and behavior of children were significantly improved from T1 to T2 in the intervention group, but not in the control group. Participants' mental health was markedly worsened in the control group. CONCLUSION: This study demonstrated that the COSP program for mothers of children with ASD improved their parental self-efficacy and mental health, and reduced their subjective sense of difficulties related to their children's behaviors. Our findings support the effectiveness of the attachment-based program for mothers of children with ASD, providing the groundwork for further studies of the attachment-based intervention for children with ASD and their families. Future studies with larger samples and randomization are also needed for direct evaluation of the improvement of children's attachment security, and for exploration of the synergistic relationship between various family support strategies and COSP. Trial Registration This trial was registered with the University Hospital Medical Information Network Clinical Trial Registry (No. UMIN000039574).

Association of adverse childhood experiences and precuneus volume with intrusive reexperiencing in autism spectrum disorder.

Compared to typically developing (TD) children, people with autism spectrum disorder (ASD) have an increased risk of adverse childhood experiences (ACEs). Exposure to ACEs is associated with adult ASD psychological comorbidities, such as posttraumatic stress disorder (PTSD). Occurrence of intrusive event reexperiencing, characteristic of PTSD, often causes social dysfunction in adults with ASD, but its pathological basis is unclear. This study examined brain regions related to the severity of intrusive reexperiencing and explored whether ACE severity was associated with that of intrusive reexperiencing and/or extracted regional gray matter volume. Forty-six individuals with ASD and 41 TD subjects underwent T1-weighted magnetic resonance imaging and evaluation of ACEs and intrusive reexperiencing. Brain regions related to the severity of intrusive reexperiencing in both groups were identified by voxel-based whole brain analyses. Associations among the severity of intrusive reexperiencing, that of ACEs, and gray matter volume were examined in both groups. The severities of intrusive reexperiencing and ACEs were significantly associated with reduced gray matter volume in the right precuneus in individuals with ASD but not in TD subjects. Although the right precuneus gray matter volume was smaller in individuals with ASD and severe ACEs than in those with mild ACEs or TD subjects, it was similar in the latter two groups. However, ACE-dependent gray matter volume reduction in the right precuneus led to intrusive reexperiencing in individuals with ASD. This suggests that exposure to ACEs is associated with right precuneus gray matter reduction, which is critical for intrusive reexperiencing in adults with ASD. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) are at increased risk of adverse childhood experiences (ACEs) and of subsequent manifestation of intrusive reexperiencing of stressful life events. The present study found that reduced gray matter volume in the right precuneus of the brain was associated with more severe intrusive reexperiencing of ACEs by individuals with ASD. These results suggest that ACEs affect neural development in the precuneus, which is the pathological basis of intrusive event reexperiencing in ASD.

Evaluating Guanfacine Hydrochloride in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adult Patients: Design, Development and Place in Therapy.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a combination of these characteristics. It is estimated to affect around 4% of adults worldwide. In the past few decades, prescriptions for ADHD drugs (psychostimulants and non-psychostimulants) have increased significantly. However, the efficacy and safety of adult ADHD medications remains controversial. Guanfacine extended-release (GXR) is a non-psychostimulant ADHD drug that is a selective α2A-adrenergic receptor agonist, first approved for treatment of adult ADHD in Japan in June 2019. Our aim was to provide an overview of GXR pharmacology and review the studies on efficacy and safety that have been conducted in adults with ADHD. The beneficial actions of guanfacine are thought to be attributed to the strengthening of prefrontal cortical network connections, which regulate attention, emotion, and behavior via the activity at post-synaptic α2A receptors. Current evidence of GXR efficacy and safety suggests that GXR is an effective monotherapy treatment option for adults with ADHD.

A Randomized Controlled Trial Evaluating the Effectiveness of a Short Video-Based Educational Program for Improving Mental Health Literacy Among Schoolteachers.

Background: Mental illness-related stigma represents a barrier to seeking and receiving appropriate mental health care. Mental health literacy (MHL) can improve mental health knowledge, decrease stigmatizing attitudes, and enhance help-seeking behavior. Starting from 2022, mental illness-related education is due to be introduced in high schools in Japan. For this current situation, we conducted a parallel group, randomized controlled trial to examine the effectiveness of MHL educational program for teachers. Methods: The educational program described in this study comprised a 50-min video lesson designed to improve teachers' MHL. All participants were schoolteachers and were assigned either to an educational group or a waitlist control group. The assessment was conducted for both groups twice: first at baseline and then at 1-h post-intervention. The outcome measures for this trial were changes in knowledge, attitudes, and intended behaviors. Results: The educational group showed a greater improvement in knowledge regarding mental health than did the control group. The program was not effective for decreasing stigma toward mental illness. However, the educational group showed an increased intention to assist students with depression. Limitations: No long-term follow-up was implemented, which means the persistence of the educational program's effect could not be determined. Further, we could not report whether the program induced a change in teachers' behaviors regarding providing support for their students. Conclusions: The short video-based MHL educational program could improve schoolteachers' MHL and increase their intention to assist students. These findings can help in the development of similar educational programs in countries/regions experiencing similar issues regarding mental health.

Suicide prevention in Japan: Government and community measures, and high-risk interventions.

Suicide is one of the most critical issues worldwide. In Japan, more than 30 000 people died by suicide every year between 1998 and 2011, and the Japanese government, local governments, and various other agencies have been working on suicide prevention programs to reduce the suicide rate. While the number of suicides is still high (more than 20 000 per year), many specialists are striving to further reduce the number of suicides in Japan. The Japanese government has played a central role in suicide prevention through the enactment of several laws, and in recent years, suicide prevention has shifted from government to community-specific measures. This review discusses the suicide prevention measures that have been taken so far: (1) policy strategies for suicide prevention by the Japanese government, (2) community suicide prevention, and (3) strategic studies for suicide prevention. Finally, as shown in the ACTION-J study, we conclude that cooperation among related organizations in the community, not just one institution, is important for future suicide prevention, especially youth suicide prevention.

The effects of maternal separation on behaviours under social-housing environments in adult male C57BL/6 mice.

Adverse experience in early life can affect the formation of neuronal circuits during postnatal development and exert long-lasting influences on neural functions that can lead to the development of a variety of psychiatric disorders including depression, anxiety disorders, and post-traumatic stress disorder. Many studies have demonstrated that daily repeated maternal separation, an animal model of early-life stress, can induce impairments in emotional behaviours and cognitive function during adolescence and adulthood. However, the behavioural phenotypes of maternally separated mice under long-term group-housing conditions are largely unknown. In this study, we applied our newly developed assay system to investigate the effects of maternal separation on behaviours under group-housing conditions during four days of continuous observations. Using our system, we found that repeated maternal separation resulted in inappropriate social distance from cagemates, altered approach preferences to others, and induced a lower rank in the time spent on the running wheel under group-housing conditions in adult male mice. Focussing on these behavioural abnormalities that appear in an environment with a social context will be important insights to understand the pathogenesis of psychiatric disorders.

A retrospective study of factors associated with persistent delirium.

BACKGROUND: It has been reported that delirium causes various problems. Many researchers have reported the risk factors associated with the onset of delirium; however, there are few reports focused on persistent delirium. This study aimed to identify the risk factors associated with persistent delirium. METHODS: A total of 573 patients hospitalised in Nara Prefecture General Medical Centre from October 2014 through September 2017 who were referred to the psychiatry consultation service were included in this study. Persistent delirium was defined as delirium lasting for 14 days or more. A retrospective study was carried out based on the patients' records. The relationship between various background factors and persistent delirium was statistically analysed. RESULTS: Of the 573 hospitalised patients, 295 were diagnosed as having delirium. Forty-six patients with persistent delirium and 181 patients with nonpersistent delirium were included in this study. Multivariable logistic regression analyses revealed that male gender, opioid analgesics use, non-opioid analgesics use, and low serum sodium were significantly and independently associated with persistent delirium. Ramelteon or trazodone was used significantly more in persistent delirium, although each use was not significant. CONCLUSION: This is the first study to reveal that male gender and use of analgesics were associated with persistent delirium in general hospital. However, as this is a case-control study and may contain bias, future cohort studies and intervention studies are needed. It is also necessary to investigate the relevance of the 'degree of pain' behind the use of analgesics.

Adverse Childhood Experience Is Associated With Disrupted White Matter Integrity in Autism Spectrum Disorder: A Diffusion Tensor Imaging Study.

Individuals with autism spectrum disorder (ASD) have an increased risk of adverse childhood experiences (ACEs) than typically developed (TD) children. Since multiple lines of studies have suggested that ACEs are related to myelination in the frontal lobe, an exposure to ACEs can be associated with white matter microstructural disruption in the frontal lobe, which may be implicated in subsequential psychological deficits after the adulthood. In this study, we investigated the relationship between ACEs and microstructural integrity on frontal lobe-related white matter tracts using diffusion tensor imaging in 63 individuals with ASD and 38 TD participants. Using a tractography-based analysis, we delineated the uncinate fasciculus (UF), dorsal cingulum (Ci), and anterior thalamic radiation (ATR), which are involved in the neural pathology of ASD, and estimated each diffusion parameter. Compared to the TD participants, individuals with ASD displayed significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the left ATR. Then, ASD individuals exposed to severe ACEs displayed higher RD than those exposed to mild ACEs and TD participants in the left ATR. Moreover, the severity of ACEs, particularly neglect, correlated with lower FA and higher RD in the left UF and ATR in individuals with ASD, which was not observed in TD participants. These results suggest that an exposure to ACEs is associated with abnormality in the frontal lobe-related white matter in ASD.