Altered white matter connectivity of ventral language networks in autism spectrum disorder: An automated fiber quantification analysis with multi-site datasets.

Comprehension and pragmatic deficits are prevalent in autism spectrum disorder (ASD) and are potentially linked to altered connectivity in the ventral language networks. However, previous magnetic resonance imaging studies have not sufficiently explored the microstructural abnormalities in the ventral fiber tracts underlying comprehension dysfunction in ASD. Additionally, the precise locations of white matter (WM) changes in the long tracts of patients with ASD remain poorly understood. In the current study, we applied the automated fiber-tract quantification (AFQ) method to investigate the fine-grained WM properties of the ventral language pathway and their relationships with comprehension and symptom manifestation in ASD. The analysis included diffusion/T1 weighted imaging data of 83 individuals with ASD and 83 age-matched typically developing (TD) controls. Case-control comparisons were performed on the diffusion metrics of the ventral tracts at both the global and point-wise levels. We also explored correlations between diffusion metrics, comprehension performance, and ASD traits, and conducted subgroup analyses based on age range to examine developmental moderating effects. Individuals with ASD exhibited remarkable hypoconnectivity in the ventral tracts, particularly in the temporal portions of the left inferior longitudinal fasciculus (ILF) and the inferior fronto-occipital fasciculus (IFOF). These WM abnormalities were associated with poor comprehension and more severe ASD symptoms. Furthermore, WM alterations in the ventral tract and their correlation with comprehension dysfunction were more prominent in younger children with ASD than in adolescents. These findings indicate that WM disruptions in the temporal portions of the left ILF/IFOF are most notable in ASD, potentially constituting the core neurological underpinnings of comprehension and communication deficits in autism. Moreover, impaired WM connectivity and comprehension ability in patients with ASD appear to improve with age.

Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study.

BACKGROUND: Neuroinflammation is associated with various chronic neurological diseases, including epilepsy; however, neuroimaging approaches for visualizing neuroinflammation have not been used in the clinical routine yet. In this study, we used the translocator protein positron emission tomography (PET) with [11C] DPA713 to investigate neuroinflammation in the epileptogenic zone in patients with child-onset focal epilepsy. METHODS: Patients with intractable focal epilepsy were recruited at the Epilepsy Center of Osaka University; those who were taking any immunosuppressants or steroids were excluded. PET images were acquired for 60 min after intravenous administration of [11C] DPA713. The PET image of [11C] DPA713 was co-registered to individual's magnetic resonance imaging (MRI), and the standardized uptake value ratio (SUVr) in regions of interest, which were created in non-lesions and lesions, was calculated using the cerebellum as a pseudo-reference region. In the case of epilepsy surgery, the correlation between SUVr in lesions and pathological findings was analyzed. RESULTS: Twenty-seven patients (mean age: 11.3 ± 6.2 years, male/female: 17/10) were included in this study. Of these, 85.1% showed increased uptake of [11C] DPA713 in the focal epileptic lesion. Three patients showed epileptic spasms, suggesting partial seizure onset, and all 18 patients with abnormal lesions on MRI were similarly highlighted by significant uptake of [11C] DPA713. DPA713-positive patients had a broad range of etiologies, including focal cortical dysplasia, tumors, infarction, and hippocampal sclerosis. Five out of nine MRI-negative patients showed abnormal [11C] DPA713 uptake. The SUVr of [11C] DPA713 in lesions was significantly higher than that in non-lesions. In seven patients who underwent epilepsy surgery, increased [11C] DPA713 uptake was associated with microglial activation. CONCLUSIONS: This study indicates that [11C] DPA713 uptake has valuable sensitivity in the identification of epileptic foci in child-onset focal epilepsy, and inflammation is implicated in the pathophysiology in the epileptic foci caused by various etiologies. Further research is required to establish diagnostic tools for identifying focal epileptogenic zones.

Abnormal cortical activation during an auditory word comprehension task in benign childhood epilepsy with centrotemporal spikes: A magnetoencephalographic study.

OBJECTIVE: Benign childhood epilepsy with centrotemporal spikes (BECTS), also known as rolandic epilepsy, has recently been reported to be associated with variable degrees of cognitive dysfunction. Many studies reported poor language ability in children with BECTS compared with healthy control children. To elucidate the harmful effects of BECTS on language cognition, we studied the magnetoencephalographic activity elicited by an auditory language comprehension task. METHODS: The participants (N = 20) included 10 children diagnosed with BECTS (aged 10.8 ±â€¯2.8 years) and 10 age-matched healthy children (control) (aged 10.6 ±â€¯1.6 years). Cognitive function was assessed using general intellectual function and language ability. In patients with BECTS, we reviewed the clinical course and electroencephalogram (EEG) findings. We recorded the cortical responses elicited by an auditory language comprehension task using magnetoencephalography (MEG). We compared those results between groups and analyzed the correlation with cognitive scores and frequency of spikes. RESULTS: The full-scale intelligence quotient (FSIQ) by the Wechsler Intelligence Scale for Children-4th edition was significantly reduced in the group with BECTS (96.4 ±â€¯12.3) compared with the control group (110.0 ±â€¯7.4). In half of the group with BECTS, the auditory comprehension score fell below the age-standard level. In the group with BECTS, the cortical activation during the task showed reduced intensity in language-associated areas such as the bilateral primary auditory cortex, left superior and mid-temporal areas, and inferior frontal area compared with those in the control group. In addition, the cortical activation in the left superior temporal area was negatively correlated with spike frequency and positively correlated with FSIQ in the group with BECTS. Conversely, the right inferior frontal and mid-temporal areas had increased the activations in the group with BECTS. From the time frequency analysis, low gamma band event-related desynchronization was reduced in the group with BECTS. CONCLUSION: Epileptic spikes negatively influenced responsiveness to the auditory language comprehension task in the language-associated cortices. These findings suggest that epileptic spikes could have a negative impact on the functional activity in rolandic areas and become a reason to change the functional development of the language network.

Tuberous sclerosis complex: Recent advances in manifestations and therapy.

Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, "a cross-sectional medical examination system," a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex-associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex.

Inter-hemispheric somatosensory coherence and parental stress in hypersensitivity at 8 months old: An electroencephalography study.

OBJECTIVE: Infant hypersensitivity affects daily challenges and parental stress. Although the crucial role of tactile sensation in infants' brain function has been highlighted, hypersensitive infants and their families lack support. Electroencephalography may be useful for understanding hypersensitivity traits. We investigated the relationship between infant perceptual hypersensitivity and parental stress, somatosensory-evoked potential (SEP), and magnitude-squared coherence (MSC) in the general population. METHODS: Infants aged 8 months (n = 63) were evaluated for hypersensitivity and parental stress using a questionnaire and for cortical activity using electroencephalography. Vibration stimuli were applied to the infant's left foot. SEP components that peaked around 150 ms (N2) and at 200 ms (P2) after stimulus onset were evaluated by amplitude and latency at the midline electrode (Cz) and MSC between the midline electrodes (C3-C4). RESULTS: Parental stress was associated with infant hypersensitivity. The latency of Cz was delayed, and C3-C4 delta MSC was high in infants with hypersensitivity. CONCLUSIONS: Increasing inter-hemispheric MSC synchrony in the stimulated condition in infants with hypersensitivity suggested atypical somatosensory cortical function. SIGNIFICANCE: These findings contribute to identifying, understanding the mechanisms of, and developing effective coping strategies for early-stage hypersensitivity.

Altered microstructural connectivity of the superior cerebellar peduncle is related to motor dysfunction in children with autistic spectrum disorders.

Many studies have reported motor impairments in autistic spectrum disorders (ASD). However, the brain mechanism underlying motor impairment in ASD remains unclear. Recent neuroimaging studies have suggested that underconnectivity between the cerebellum and other brain regions contributes to the features of ASD. In this study, we investigated the microstructural integrity of the cerebellar pathways, including the superior, middle, and inferior cerebellar peduncles, of children with and without ASD by using diffusion tensor imaging (DTI) tractography to determine whether the microstructural integrity of the cerebellar pathways is related to motor function in children with ASD. Thirteen children with ASD and 11 age-, gender-, handedness-, and IQ-matched typically developing (TD) controls were enrolled in this study. DTI outcome measurements, such as fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), for the cerebellar pathways were calculated. The Movement Assessment Battery for Children 2 (M-ABC 2) was used for assessing motor functions. There were no significant differences between the two groups in RD. However, compared to the TD subjects, patients with ASD had a significantly lower FA in the right superior cerebellar peduncle and lower AD in the left superior cerebellar peduncle, in addition to a significantly lower score in ball skills and the total test score of M-ABC 2. There was a significant positive correlation between the total test score of M-ABC 2 and FA in the right superior cerebellar peduncle in the ASD group. These findings suggest that the altered microstructural integrity of the superior cerebellar peduncle may be related to motor impairment in ASD.

A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia.

We reported on a male patient with rare leukoencephalopathy and skeletal abnormalities. The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age. At 4 years of age, he was diagnosed as hypomyelination with skeletal abnormalities from clinical features, brain magnetic resonance imaging (MRI) and skeletal X-rays. His brain MRI revealed diffuse hypomyelination. These findings suggested the classical type of Pelizaeus-Merzbacher disease (PMD) caused by proteolipid protein (PLP)-1 gene or Pelizaeus-Merzbacher-like disease (PMLD). However, we found neither mutation nor duplication of PLP-1. The patient had severe growth retardation and general skeletal dysplasia compatible with spondylo-epi-metaphyseal dysplasia; however the mutation of discoidin domain receptor (DDR) 2 gene was absent. The co-morbidity of hypomyelination with skeletal abnormalities is rare. We performed array CGH and no causal copy number variation was recognized. Alternatively, this condition may have been caused by a mutation of the gene encoding a molecule that functions in both cerebral myelination and skeletal development.

[Cyclophosphamide pulse therapy effective for childhood-onset refractory multiple sclerosis: a case report].

We report a case of a 15-year-old girl with relapsing-remitting multiple sclerosis (MS) who received cyclophosphamide pulse therapy. At the age of 5 years, she displayed symptoms such as headache and unconsciousness after varicella infection as the first episode of MS. She had been treated with methylprednisolone pulse therapy, intravenous immunoglobulin, interferon-beta1b, and azathioprine. However, she had relapsed 12 times by the age of 15 years. At this time, she showed weakness and severe paralysis of her left leg, and even 1 month after methylprednisolone pulse therapy, she still had gait impairment and showed gadolinium-enhanced lesion on brain magnetic resonance imaging. We then started cyclophosphamide pulse therapy (600 mg/m2) once a month for 12 months combined with interferon-beta1a. She had no serious side effects and she could walk again after 4 months on cyclophosphamide treatment. She has been free from relapse for 2 years and 8 months until the present time. Although only a few studies have indicated the efficacy of cyclophosphamide pulse therapy for childhood MS, we consider careful use of cyclophosphamide could be one of the options for refractory childhood MS.

Examining normative values using the Cambridge neuropsychological test automated battery and developmental traits of executive functions among elementary school-aged children in Japan.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computerized and child-friendly neuropsychological assessment battery that includes subtests aimed at evaluating some aspects of executive functions. Using the CANTAB, this study aims to establish normative values based on the aspects of executive functions among school-aged children in Japan. The participants included 234 children (135 boys and 99 girls aged 6-12 years) enrolled in regular classes, without any clinical records of developmental disorders or educational support. The participants were grouped according to age (6-7, 8-9, and 10-12 years). Four CANTAB subtests, including spatial working memory (SWM) to assess spatial working memory, Stockings of Cambridge (SOC) to evaluate planning, intra/extradimensional set shift (IED) to evaluate attentional set shifting and flexibility, and stop signal task (SST) to evaluate inhibition, were administered to each participant. The results showed that performance in all the CANTAB subtests administered changed with age. Among the subtests, compared with performances in the SOC and IED, those in the SWM and SST improved earlier, thereby indicating that spatial working memory and inhibition develop earlier than planning as well as attentional set shifting and flexibility. Additionally, in the SST subtest, girls made fewer errors than boys did in the 6-7 years group. This study presents normative data of four CANTAB subtests according to age and sex among school-aged children in Japan. We expect that the findings will be used to develop effective tools for the early detection of and support for children with executive dysfunction.

Extension of microglial activation is associated with epilepsy and cognitive dysfunction in Tuberous sclerosis complex: A TSPO-PET study.

BACKGROUND AND OBJECTIVES: Neuroinflammation contributes to the severity of various neurological disorders, including epilepsy. Tuberous sclerosis complex (TSC) is a condition that results in the overactivation of the mammalian target of rapamycin (mTOR) pathway, which has been linked to the activation of microglia responsible for neuroinflammation. To clarify the involvement of neuroinflammation in the neuropathophysiology of TSC, we performed a positron emission tomography (PET) study using the translocator protein (TSPO) radioligand, [11C] DPA713, and investigated microglial activation in relation to neurological manifestations, especially epilepsy and cognitive function. METHODS: This cross-sectional study included 18 patients with TSC (6 in the no-seizure group, 6 in the refractory seizure group, and 6 in the mTOR-inhibitor [mTOR-i] group). All participants underwent [11C] DPA713-PET. PET results were superimposed with a 3D T2-weighted fluid-attenuated inversion-recovery (FLAIR) and T1-weighted image (T1WI) to evaluate the location of cortical tubers. Microglial activation was assessed using the standardized uptake value ratio (SUVr) of DPA713 binding. The volume ratio of the DPA713-positive area to the intracranial volume (volume ratio of DPA713/ICV) was calculated to evaluate the extent of microglial activation. A correlation analysis was performed to examine the relationship between volume ratio of DPA713/ICV and severity of epilepsy and cognitive function. RESULTS: Most cortical tubers with hyperintensity on FLAIR and hypo- or isointensity on T1WI showed microglial activation. The extent of microglial activation was significantly greater in the refractory seizure group than in the no-seizure or mTOR-i groups (p < 0.001). The extent of microglial activation in subjects without mTOR-i treatment correlated positively with epilepsy severity (r = 0.822, P = 0.001) and negatively with cognitive function (r = -0.846, p = 0.001), but these correlations were not present in the mTOR-i group (r = 0.232, P = 0.658, r = 0.371, P = 0.469, respectively). CONCLUSION: Neuroinflammation is associated with the severity of epilepsy and cognitive dysfunction in brains with TSC. mTOR-i may suppress the extent of neuroinflammation in TSC. Investigating the spread of microglial activation using TSPO-PET in these patients may help to predict the progression of neuropathy by assessing the degree of neuroinflammation and therefore be useful for determining how aggressive the treatment should be and in assessing the effectiveness of such treatment in patients with TSC.

Clinical Factors Related to Outcomes in Pediatric Epilepsy Surgery: Insight into Predictors of Poor Surgical Outcome.

Successful surgery for drug-resistant pediatric epilepsy can facilitate motor and cognitive development and improve quality of life by resolution or reduction of epileptic seizures. Therefore, surgery should be considered early in the disease course. However, in some cases, the estimated surgical outcomes are not achieved, and additional surgical treatments are considered. In this study, we investigated the clinical factors related with such unsatisfactory outcomes.We reviewed the clinical data of 92 patients who underwent 112 surgical procedures (69 resection and 53 palliation procedures). Surgical outcomes were assessed according to the postoperative disease status, which was classified as good, controlled, and poor. The following clinical factors were analyzed in relation to surgical outcome: sex, age at onset, etiology (malformation of cortical development, tumor, temporal lobe epilepsy, scar, inflammation, and non-lesional epilepsy), presence of genetic cause, and history of developmental epileptic encephalopathy. At a median of 59 (30-81.25) months after the initial surgery, the disease status was good in 38 (41%), controlled in 39 (42%), and poor in 15 (16%) patients. Among the evaluated factors, etiology exhibited the strongest correlation with surgical outcomes. Tumor-induced and temporal lobe epilepsy were correlated with good, whereas malformation of cortical development, early seizure onset, and presence of genetic cause were correlated with poor disease status. Although epilepsy surgery for the patients who present with the latter factors is challenging, these patients demonstrate a greater need for surgical treatment. Hence, development of more effective surgical options is warranted, including palliative procedures.

Child Developmental MRI (CDM) project: protocol for a multi-centre, cross-sectional study on elucidating the pathophysiology of attention-deficit/hyperactivity disorder and autism spectrum disorder through a multi-dimensional approach.

INTRODUCTION: Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have demonstrated differences in extensive brain structure, activity and network. However, there remains heterogeneity and inconsistency across these findings, presumably because of the diversity of the disorders themselves, small sample sizes, and site and parameter differences in MRI scanners, and their overall pathogenesis remains unclear. To address these gaps in the literature, we will apply the travelling-subject approach to correct site differences in MRI scanners and clarify brain structure and network characteristics of children with ADHD and ASD using large samples collected in a multi-centre collaboration. In addition, we will investigate the relationship between these characteristics and genetic, epigenetic, biochemical markers, and behavioural and psychological measures. METHODS AND ANALYSIS: We will collect resting-state functional MRI (fMRI) and T1-weighted and diffusion-weighted MRI data from 15 healthy adults as travelling subjects and 300 children (ADHD, n=100; ASD, n=100; and typical development, n=100) with multi-dimensional assessments. We will also apply data from more than 1000 samples acquired in our previous neuroimaging studies on ADHD and ASD. ETHICS AND DISSEMINATION: The study protocol has been approved by the Research Ethics Committee of the University of Fukui Hospital (approval no: 20220601). Our study findings will be submitted to scientific peer-reviewed journals and conferences.

Association between cerebrospinal fluid parameters and developmental and neurological status in glucose transporter 1 deficiency syndrome.

OBJECTIVE: In glucose transporter 1 deficiency syndrome (Glut1DS), cerebrospinal fluid glucose (CSFG) and CSFG to blood glucose ratio (CBGR) show significant differences among groups classified by phenotype or genotype. The purpose of this study was to investigate the association between these biochemical parameters and Glut1DS severity. METHODS: The medical records of 45 patients who visited Osaka University Hospital between March 2004 and December 2021 were retrospectively examined. Neurological status was determined using the developmental quotient (DQ), assessed using the Kyoto Scale of Psychological Development 2001, and the Scale for the Assessment and Rating of Ataxia (SARA). CSF parameters included CSFG, CBGR, and CSF lactate (CSFL). RESULTS: CSF was collected from 41 patients, and DQ and SARA were assessed in 24 and 27 patients, respectively. Simple regression analysis showed moderate associations between neurological status and biochemical parameters. CSFG resulted in a higher R2 than CBGR in these analyses. CSF parameters acquired during the first year of life were not comparable to those acquired later. CSFL was measured in 16 patients (DQ and SARA in 11 and 14 patients, respectively). Although simple regression analysis also showed moderate associations between neurological status and CSFG and CSFL, the multiple regression analysis for DQ and SARA resulted in strong associations through the use of a combination of CSFG and CSFL as explanatory variables. CONCLUSION: The severity of Glut1DS can be predicted from CSF parameters. Glucose and lactate are independent contributors to the developmental and neurological status in Glut1DS.

[Effects of botulinum toxin therapy for respiratory distress in patients with cervical hypertonia].

Botulinum toxin A (BTX-A) therapy has been approved as a first-line therapy for spastic torticollis. However it has been suggested as that its use in patients with respiratory distress should be decided cautiously. We treated 5 patients with abnormal posture, cervical hypertonia and obstructive respiratory distress by BTX-A, and analyzed its efficacy for respiratory distress by their Tsui score and respiratory status after BTX-A therapy. All 5 patients clinically had some degree of dysphagia before BTX-A therapy. Cervical hypertonia and induced abnormal posture were improved in all patients. The youngest patient could control muscle tone after only 2 doses of BTX-A and subsequently maintained a good condition without additional BTX-A. BTX-A therapy can decrease torsion and hyperextension of the upper respiratory tract by reducing cervical hypertonia. Consequently, it may improve respiratory status. On the other hand, mild dysphagia and excessive salivation was noted in one patient for each symptom. It is safe to avoid BTX-A invasion to the anterior muscle of neck and rapid changes in the swallowing pattern.

Atypical structural connectivity of language networks in autism spectrum disorder: A meta-analysis of diffusion tensor imaging studies.

Patients with autism spectrum disorder (ASD) often show pervasive and complex language impairments that are closely associated with aberrant structural connectivity of language networks. However, the characteristics of white matter connectivity in ASD have remained inconclusive in previous diffusion tensor imaging (DTI) studies. The current meta-analysis aimed to comprehensively elucidate the abnormality in language-related white matter connectivity in individuals with ASD. We searched PubMed, Web of Science, Scopus, and Medline databases to identify relevant studies. The standardized mean difference was calculated to measure the pooled difference in DTI metrics in each tract between the ASD and typically developing (TD) groups. The moderating effects of age, sex, language ability, and symptom severity were investigated using subgroup and meta-regression analysis. Thirty-three DTI studies involving 831 individuals with ASD and 836 TD controls were included in the meta-analysis. ASD subjects showed significantly lower fractional anisotropy or higher mean diffusivity across language-associated tracts than TD controls. These abnormalities tended to be more prominent in the left language networks than in the right. In addition, children with ASD exhibit more pronounced and pervasive disturbances in white matter connectivity than adults. These results support the under-connectivity hypothesis and demonstrate the widespread abnormal microstructure of language-related tracts in patients with ASD. Otherwise, white matter abnormalities in the autistic brain could vary depending on the developmental stage and hemisphere. LAY SUMMARY: This meta-analysis explored abnormalities in white matter connectivity in language networks of individuals with ASD. Significantly reduced white matter integrity was found in all language-associated tracts in subjects with ASD compared with TD controls. In addition, structural disturbances of language networks in the autistic brain exhibit a leftward tendency, and more prominent abnormalities are observed in younger people with ASD than in adults.

A preliminary study of sleep spindles across non-rapid eye movement sleep stages in children with autism spectrum disorder.

Study Objectives: Sleep spindles play a crucial role in multiple neuronal network functions. Initiation and termination of spindles are regulated by the thalamic reticular nucleus and thalamocortical network, and the spindle can be an index for brain organization. We conducted a preliminary study of the parameters of sleep spindles, focusing on sleep-stage temporal distribution in children with autism spectrum disorder (ASD) with normal intelligence/developmental quotients. Methods: We performed overnight polysomnography in 14 children with ASD (4-10 years) with normal full-scale intelligence quotient/developmental quotient (≥75) and 14 community samples (CS) of children. Sleep stages were scored according to the Rechtschaffen and Kales criteria. Spindle parameters were quantified and compared between these groups and the identified subgroups. Results: Sleep parameters did not differ between the ASD and CS groups, except for a higher rate of rapid eye movement (REM) sleep duration in ASD. Spindle parameters did not significantly differ between the groups, but spindle density was distributed in a broader range in the ASD group. Five children with ASD had a higher spindle density in stage 3 than in stage 2. The ratio of spindle density in stage 3 to that in stage 2 (stage 3/2 ratio) was significantly higher in ASD than in CS cases. Conclusions: The lower spindle density in stage 2 and relatively higher density in stage 3 in children with ASD may represent an abnormal generation of spindles due to insufficient maturation of the thalamic reticular nucleus and thalamocortical network.

Abnormal White Matter Microstructure in the Limbic System Is Associated With Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders.

Objective: Tuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI). Methods: A total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers. Results: The TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC. Conclusion: The disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

Fully-Automated Spike Detection and Dipole Analysis of Epileptic MEG Using Deep Learning.

Magnetoencephalography (MEG) is a useful tool for clinically evaluating the localization of interictal spikes. Neurophysiologists visually identify spikes from the MEG waveforms and estimate the equivalent current dipoles (ECD). However, presently, these analyses are manually performed by neurophysiologists and are time-consuming. Another problem is that spike identification from MEG waveforms largely depends on neurophysiologists' skills and experiences. These problems cause poor cost-effectiveness in clinical MEG examination. To overcome these problems, we fully automated spike identification and ECD estimation using a deep learning approach fully automated AI-based MEG interictal epileptiform discharge identification and ECD estimation (FAMED). We applied a semantic segmentation method, which is an image processing technique, to identify the appropriate times between spike onset and peak and to select appropriate sensors for ECD estimation. FAMED was trained and evaluated using clinical MEG data acquired from 375 patients. FAMED training was performed in two stages: in the first stage, a classification network was learned, and in the second stage, a segmentation network that extended the classification network was learned. The classification network had a mean AUC of 0.9868 (10-fold patient-wise cross-validation); the sensitivity and specificity were 0.7952 and 0.9971, respectively. The median distance between the ECDs estimated by the neurophysiologists and those using FAMED was 0.63 cm. Thus, the performance of FAMED is comparable to that of neurophysiologists, and it can contribute to the efficiency and consistency of MEG ECD analysis.

Abnormal cortical responses elicited by audiovisual movies in patients with autism spectrum disorder with atypical sensory behavior: A magnetoencephalographic study.

BACKGROUND: Atypical sensory behavior disrupts behavioral adaptation in children with autism spectrum disorder (ASD); however, neural correlates of sensory dysfunction using magnetoencephalography (MEG) remain unclear. METHOD: We used MEG to measure the cortical activation elicited by visual (uni)/audiovisual (multisensory) movies in 46 children (7-14 years) were included in final analysis: 13 boys with atypical audiovisual behavior in ASD (AAV+), 10 without this condition, and 23 age-matched typically developing boys. RESULTS: The AAV+ group demonstrated an increase in the cortical activation in the bilateral insula in response to unisensory movies and in the left occipital, right superior temporal sulcus (rSTS), and temporal regions to multisensory movies. These increased responses were correlated with severity of the sensory impairment. Increased theta-low gamma oscillations were observed in the rSTS in AAV+. CONCLUSION: The findings suggest that AAV is attributed to atypical neural networks centered on the rSTS.