Correlation between autistic traits and brain functional connectivity in preschoolers with autism spectrum disorder: a resting state MEG study.

BACKGROUND: Neurophysiological studies recognized that Autism Spectrum Disorder (ASD) is associated with altered patterns of over- and under-connectivity. However, little is known about network organization in children with ASD in the early phases of development and its correlation with the severity of core autistic features. METHODS: The present study aimed at investigating the association between brain connectivity derived from MEG signals and severity of ASD traits measured with different diagnostic clinical scales, in a sample of 16 children with ASD aged 2 to 6 years. RESULTS: A significant correlation emerged between connectivity strength in cortical brain areas implicated in several resting state networks (Default mode, Central executive, Salience, Visual and Sensorimotor) and the severity of communication anomalies, social interaction problems, social affect problems, and repetitive behaviors. Seed analysis revealed that this pattern of correlation was mainly caused by global rather than local effects. CONCLUSIONS: The present evidence suggests that altered connectivity strength in several resting state networks is related to clinical features and may contribute to neurofunctional correlates of ASD. Future studies implementing the same method on a wider and stratified sample may further support functional connectivity as a possible biomarker of the condition.

Cerebellar cognitive affective syndrome with long-term features of autism spectrum disorder: evidence in a 9-year-old girl after vermian medulloblastoma surgery.

The time course of socio-communicative disturbances in children after posterior fossa tumor resection is variable in clinical reports, and its assessment may help to understand the role of the cerebellum in the pathogenesis of socio-communicative disorders and improve rehabilitation plans. We report the 3-year cognitive-behavioral follow-up of a female patient (LZ) who underwent surgical ablation of the vermis due to medulloblastoma at age 9. LZ developed a severe post-operative Cerebellar Cognitive Affective Syndrome (CCAS) with cognitive-executive dysfunctions and behavioral alterations resembling an Autism Spectrum Disorder (ASD)-like syndrome. The lack of empathy and reduced ability to recognize others' intentions and mental states persisted at follow-up evaluations, as did language alterations. The present case report evidenced that lesions affecting cerebellar and vermal lobules may cause severe CCAS and impairment of social skills overlapping with that observed in ASD. This case is significant in its clinical features, revealing long-term social impairment, while the cognitive, linguistic, and executive functioning improved over time. Prospective case studies should plan the evaluation of symptoms of ASD within the clinical longitudinal assessment.

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

PURPOSE: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. METHODS: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. RESULTS: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. CONCLUSION: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.

Cognitive and Behavioral Outcome of Pediatric Low-Grade Central Nervous System Tumors Treated Only with Surgery: A Single Center Experience.

BACKGROUND: The present mono-institutional report aimed to describe the cognitive and behavioral outcomes of low-grade central nervous system (CNS) tumors in a cohort of children treated exclusively with surgical intervention. METHODS: Medical records from 2000-2020 were retrospectively analyzed. We included 38 children (mean age at first evaluation 8 years and 3 months, 16 females) who had undergone presurgical cognitive-behavioral evaluation and/or at least 6 months follow-up. Exclusion criteria were a history of traumatic brain injury, stroke, cerebral palsy or cancer-predisposing syndromes. RESULTS: The sample presented cognitive abilities and behavioral functioning in the normal range, with weaknesses in verbal working memory and processing speed. The obtained results suggest that cognitive and behavioral functioning is related to pre-treatment variables (younger age at symptoms' onset, glioneuronal histological type, cortical location with preoperative seizures), timing of surgery and seizure control after surgery, and is stable when controlling for a preoperative cognitive and behavioral baseline. Younger age at onset is confirmed as a particular vulnerability in determining cognitive sequelae, and children at older ages or at longer postsurgical follow-up are at higher risk for developing behavioral disturbances. CONCLUSIONS: Timely treatment is an important factor influencing the global outcome and daily functioning of the patients. Preoperative and regular postsurgical cognitive and behavioral assessment, also several years after surgery, should be included in standard clinical practices.

Task-related functional neuroimaging contribution to sex/gender differences in cognition and emotion during development.

Recent research has shown that sex/gender (s/g) influences on cognitive functions and related brain anatomy, functional responses, and connectivity are less clear than previously assumed, and most studies investigated adult population. In this mini-review, we summarize research progress in the study of s/g differences in the human brain function as investigated by neuroimaging methods adopting a developmental perspective. In particular, we review original studies published from 2000 to 2021 investigating s/g differences in task-related brain functional activation and connectivity in healthy children and adolescents. We summarize results about studies in the domains of language, visuospatial ability, social cognition, and executive functions. Overall, a clear relation between cognition and brain activation or connectivity pattern is far from being established and the few coherent results should be considered exploratory, despite in some cases, brain function seems to present specific patterns in comparison with what reported in adults. Moreover, future studies should address methodological limitations, such as fragmentation of tasks, lack of control for confounding variables, and lack of longitudinal designs to study developmental trajectories.

CGH Findings in Children with Complex and Essential Autistic Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a strong genetic basis. We accurately assessed 209 ASD subjects, categorized in complex (47) and essential (162), and performed array comparative genomic hybridization to identify pathogenic and recurrent Copy Number Variants (CNVs). We found 117 CNVs in 75 patients, 11 classified as pathogenic. The complex ASD subjects have higher frequency of pathogenic CNVs with a diagnostic yield of 12.8%. Familiality, cognitive and verbal abilities, severity of autistic symptoms, neuroimaging and neurophysiological findings are not related to genetic data. This study identifies loci of interest for ASD and highlights the importance of a careful phenotypic characterization, as complex ASD is related to higher rate of pathogenic CNVs.

Sex and gender difference in cognitive and behavioral studies in developmental age: An introduction.

This paper introduces a special issue focused on sex and gender (s/g) cognitive/behavioral differences at developmental ages providing an overview of this multifaceted and debated topic. It will provide a description of the biological systems that are strongly interconnected to generate s/g differences, that is, genetic determinants, sex hormones, differences in brain structure, organization, and/or function, inherited or modifiable under environmental pressures. Developmental studies are rare. Some addressed whether s/g differences in cognitive/behavioral characteristics are evident early in life and are consistent throughout development, entailing that s/g differences can follow the evolving steps in girls and boys in different domains. The data are far from being homogeneous and consistent about s/g difference in language, social skills, and visuo/spatial abilities. The differences are small, often with overlapping performances, similar to what is seen in adulthood. Given that several variables and the interactions between them are implicated, further longitudinal studies adopting adequate assessment tools, very large size multicultural samples stratified in different, well-sized and precise age groups, considering biological and sociocultural variables, are needed. Due to the complexity of the issue, there is still the need to support and adopt an s/g difference approach also in cognitive and behavioral studies at developmental ages. Finally, these studies have not only scientific importance and relevant cultural, anthropological, and social implications, but are also useful for pedagogical programming as well as for the study of the different susceptibility to develop CNS diseases and consequently to promote different therapies and treatments.

Sex influences on the neurocognitive outcome of preterm children.

This article presents a revision of the literature regarding the influence of sex differences on the recovery and long-term behavioral and cognitive outcomes of preterm children. After initial discussion of some methodological concerns, the literature regarding the concept of "male disadvantage," which is often used when talking about early neurological and psychomotor outcomes in preterm children, is presented. Subsequently, the literature data on sex-related differences in preterm children are discussed, focusing on their influence on the developmental pathways of cognition, language, executive function, behavior and affect, and response to rehabilitation therapies. Finally, evidence about brain structural and connectivity correlates of sex differences in the brain of preterm survivors is taken into account. Although visuo-spatial and visuo-perceptual functioning is widely studied in the preterm child and is strongly sex specific, little to no data are available regarding male-female differences in preterm children and the interaction effect between sex and preterm birth. For this reason, original data analyses of male-female differences in visuo-spatial performance from a small sample of preterm children are also presented.

Brain Tumors in NF1 Children: Influence on Neurocognitive and Behavioral Outcome.

Neurofibromatosis type-1 (NF1) is a monogenic tumor-predisposition syndrome creating a wide variety of cognitive and behavioral abnormalities, such as decrease in cognitive functioning, deficits in visuospatial processing, attention, and social functioning. NF1 patients are at risk to develop neurofibromas and other tumors, such as optic pathway gliomas and other tumors of the central nervous system. Few studies have investigated the impact of an additional diagnosis of brain tumor on the cognitive outcome of children with NF1, showing unclear results and without controlling by the effect of surgery, radio- or chemotherapy. In the present mono-institutional study, we compared the behavioral and cognitive outcomes of 26 children with neurofibromatosis alone (NF1) with two age-matched groups of 26 children diagnosed with NF1 and untreated optic pathway glioma (NF1 + OPG) and 19 children with NF1 and untreated other central nervous system tumors (NF1 + CT). NF1 + CT and NF1 + OPG showed significantly impaired cognitive abilities compared to NF1 group, with weaknesses in visuo-spatial abilities, visual scanning and verbal working memory, while general verbal abilities are preserved. Moreover, NF1 + OPG patients present more frequent internalizing problems and increased oppositional-deviant behaviors. These results suggest that the co-diagnosis of a brain tumor in NF1 children may partially worsen the cognitive and emotional outcome.

Language Cerebro-cerebellar Reorganization in Children After Surgery of Right Cerebellar Astrocytoma: a fMRI Study.

Language processing depends on an integrated circuit involving the left supratentorial language areas and the right posterior lateral cerebellar hemisphere (lobule VI, lobule VII, Crus I, and Crus II). Reorganization of the language system after lesions of the cerebral language areas includes also cerebellar relocation. This is the first study assessing functional language reorganization after lesions concerning primarily the cerebellum, using a fMRI paradigm of phonological covert word production task in six children operated for right cerebellar astrocytoma and in 15 typically developing children. We found right cerebellar and left frontal activations in healthy controls and high variability of reorganizational patterns in patients with early right cerebellar lesion. Also lesions not located in the areas typically involved in language tasks (Crus I and Crus II) can cause reorganization between the two hemispheres or hemispheric language reinforcement of the original lateralization. We discuss the role of several variables in determining the reorganizational pattern such as the site, extension, and timing of surgery. No variables revealed as predictors, suggesting that co-occurring influence of other biological and/or pathological factors are not yet demonstrated. Lesions in the postero-lateral cerebellum seem related to less efficient language performances, as an indicator of the system's functioning.

Spontaneous MRI improvement and absence of cerebral calcification in Aicardi-Goutières syndrome: Diagnostic and disease-monitoring implications.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare genetic leukoencephalopathy related to inappropriate activation of type I interferon. Neuroradiological findings are typically characterized by white matter abnormalities, cerebral atrophy and cerebral calcification. The disease usually manifests itself during the first year of life in the form of an initial "encephalitic-like" phase followed by a chronic phase of stabilization of the neurological signs. Recently new therapeutic strategies have been proposed aimed at blocking the abnormal activation of the interferon cascade. MATERIALS AND METHODS: We reviewed clinical and MRI findings in three young RNASEH2B-mutated patients studied with serial CT and MRI studies. RESULTS: All three patients presented clinical and MRI features consistent with AGS but, very unexpectedly, an improving neuroradiological course. In patient 1, the MRI improvement was noted some months after treatment with high-dose steroid and IVIg treatment; in patients 2 and 3 it occurred spontaneously. Patient 2 did not show cerebral calcification on CT images. CONCLUSIONS: Our series highlights the possibility of spontaneous neuroradiological improvement in AGS2 patients, as well as the possibility of absence of cerebral calcification in AGS. The study underlines the need for extreme caution when using MRI as an outcome measure in therapeutic trials specific for this disease. MRI follow-up studies in larger series are necessary to describe the natural course of AGS.

Visuoperceptual Impairment in Children with NF1: From Early Visual Processing to Procedural Strategies.

Visual-spatial impairment has long been considered a hallmark feature of neurofibromatosis type 1 (NF1). No study investigating the cognitive and neuropsychological profile of NF1 used the Rey Complex Figure Test (RCFT) task as the primary measure of visual-perceptual abilities taking into consideration all functions involved including the strategic processing style. We compared 18 children with NF1, 17 siblings (S), and 18 typically developing children (TD) at intelligence scale and RCFT copy, recall, and recognition trials; we also evaluated the copy strategy as a measure of a visual-processing style. Children with NF1 had normal total IQ, with cognitive weaknesses in the perceptual organization and working memory in line with the existing literature. At the RCFT copy, immediate and delay recall scores are significantly lower in NF1 than S and TD, while recognition is in the normal range in all groups. Copy style was poor and less efficient in children with NF1 and correlated to copy and recall ability, but the effect of the group in the RCFT copy and recall remained significantly controlling for strategic approach. The present study confirms visuospatial impairment in children with NF1, due to a deficit in perceptual analysis of shape and their spatial features, in visuomotor integration efficiency and strategies, in recall memory, while recognition memory is preserved. A more configural/holistic style may facilitate both the visual-perceptual and visuomotor ability and the recall process. Visuoperceptual impairment in NF1 seems to be a unified process from early visual processing to higher order functions (planning, strategy, and executive functioning).

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Hemispheric language organization after congenital left brain lesions: A comparison between functional transcranial Doppler and functional MRI.

This study investigated whether functional transcranial Doppler ultrasound (fTCD) is a suitable tool for studying hemispheric lateralization of language in patients with pre-perinatal left hemisphere (LH) lesions and right hemiparesis. Eighteen left-hemisphere-damaged children and young adults and 18 healthy controls were assessed by fTCD and fMRI to evaluate hemispheric activation during two language tasks: a fTCD animation description task and a fMRI covert rhyme generation task. Lateralization indices (LIs), measured by the two methods, differed significantly between the two groups, for a clear LH dominance in healthy participants and a prevalent activation of right hemisphere in more than 80% of brain-damaged patients. Distribution of participants in terms of left, right, and bilateral lateralization was highly concordant between fTCD and fMRI values. Moreover, right hemisphere language dominance in patients with left hemispheric lesions was significantly associated with severity of cortical and subcortical damage in LH. This study suggests that fTCD is an easily applicable tool that might be a valid alternative to fMRI for large-scale studies of patients with congenital brain lesions.

Cognitive aspects: sequencing, behavior, and executive functions.

The question posed today is not whether the cerebellum plays a role in cognition, but instead, how the cerebellum contributes to cognitive processes, even in the developmental age. The central role of the cerebellum in many areas of human abilities, motor as well as cognitive, in childhood as well as in adulthood, is well established but cerebellar basic functioning is still not clear and is much debated. Of particular interest is the changing face of cerebellar influence on motor, higher cognitive, and behavioral functioning when adult and developmental lesions are compared. The idea that the cerebellum might play quite different roles during development and in adulthood has been proposed, and evidence from experimental and clinical literature has been provided, including for sequencing, behavioral aspects, and executive functions Still, more data are needed to fully understand the changes of cerebrocerebellar interactions within the segregated loops which connect cerebrum and cerebellum, not only between childhood and adulthood but also in health and disease.

The neuropsychology of basal ganglia.

Basal ganglia are subcortical structures specialized at very early age, functionally different according to the right or left side. They are part of complex distributed network composed by parallel segregated loops where specific information are processed and open loops where different information are integrated. These loops are connected to specialized cortical areas thus entering into distributed processing of higher order cognitive functions and behaviours. Lesion or malfunction of basal ganglia nuclei cause deficits in different neuropsychological functions and neurobehavioural diseases, such Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, Tourette syndrome, etc., for the reciprocal connections from and to the limbic system and the frontal system. Basal ganglia have a computational functioning, working by activation and inhibition sequences, coded in time and space and regulated by inhibitory and excitatory mechanisms, with such accuracy to guarantee an effective and elegant product.

Implicit learning deficit in children with Duchenne muscular dystrophy: Evidence for a cerebellar cognitive impairment?

This study aimed at comparing implicit sequence learning in individuals affected by Duchenne Muscular Dystrophy without intellectual disability and age-matched typically developing children. A modified version of the Serial Reaction Time task was administered to 32 Duchenne children and 37 controls of comparable chronological age. The Duchenne group showed a reduced rate of implicit learning even if in the absence of global intellectual disability. This finding provides further evidence of the involvement of specific aspects of cognitive function in Duchenne muscular dystrophy and on its possible neurobiological substrate.

Intensive strength and balance training with the Kinect console (Xbox 360) in a patient with CMT1A.

BACKGROUND: Effective drugs for type 1A Charcot-Marie-Tooth (CMT1A) disease are not available. Various forms of moderate exercise are beneficial, but few data are available on the effectiveness of exercise in CMT1A children. AIM: To investigate the feasibility and effectiveness of exercises to improve ankle strength and limb function in a child with CMT1A. SETTING: Outpatient clinic. POPULATION: Nine-year-old boy with CMT1A. METHODS: The rehabilitation program consisted of ankle exercises and Kinect videogame-directed physical activities (using an Xbox 360 console/movement sensor) that aimed to improve balance and limb strength. The program was given 3 times a week for 5 weeks. The child was assessed at baseline, after 5 weeks, and 3 and 6 months after. RESULTS: By the end of follow-up, child balance and endurance had improved, but ankle strength did not. CONCLUSIONS: The encouraging results for balance and endurance justify further studies on videogame-directed activities in CMT1A children/adolescents.

The Key Search Subtest of the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C) Instrument Reveals Impaired Planning Without External Constraints in Children With Neurofibromatosis Type 1.

Studies of executive function and its relationship with brain T2-weighted hyperintensities in children with neurofibromatosis type 1 (NF1) have yielded inconsistent results. We examined 16 children with NF1 aged 8 to 15 years, of normal intelligence, and compared their findings to those of 16 siblings and 16 typically developing children using the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C). NF1 patients had an adequate overall score at BADS-C, but showed significantly lower performance than typical peers in the Key Search subtest. This is a task that must be solved without any given rules, in which subjects must devise a strategy and an efficient search pattern transferable to other similar real situations. The Key Search scores were not correlated with number and signal characteristics of T2-weighted hyperintensities. Planning without external indications is impaired in children with NF1 because they have to rely entirely on self-organization and monitoring; this study provides information for remediation programs designed to improve functioning in daily life.

Cognitive, adaptive, and behavioral features in Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so-called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty-four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long-term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability. © 2016 Wiley Periodicals, Inc.